The bacterium Chlamydia trachomatis is a common sexually transmitted disease agent, with 4,000,000 new cases/year in the US. C. pneumoniae is the most common cause of community-acquired pneumonia in the US;>90% of the US population has been infected with C. pneumoniae by age 40. Chlamydial infection is often inapparent and can persist for years, causing diseases ranging from mild inflammation to pneumonia or life-threatening ectopic pregnancy. C. trachomatis genital infection has been linked to cervical cancer, either directly or as a co-factor with Human Papilloma Virus (HPV). Other chlamydial infections have also been recently linked to various cancers: C. pneumoniae infection has been associated with increased lung cancer risk and C. psittaci infection with development of ocular adnexal lymphoma. When chlamydiae-infected cells divide, the inclusion remains within one daughter cell. Thus, at least one daughter cell survives unless it is re-infected. Any host genetic alterations that occur during chlamydial infection could, therefore, be passed to the surviving daughter cell. Recently, Grieshaber et al demonstrated that chlamydial infection increases the frequency of mitotic spindle abnormalities and aberrant chromosomal segregation in dividing human epithelial cells. Other studies have demonstrated that chlamydiae-infected host cells produce increased quantities of free radicals, which can damage DNA and have been strongly linked to both cancer and aging. These reports suggest that chlamydial infection may increase the host cell nuclear mutation rate or that in surrounding, uninfected epithelial cells. In this study, we will test two hypotheses: #1) that chlamydial infection increases the nuclear DNA mutation frequency within human cells;and #2) that chlamydial infection alters expression, distribution or phosphorylation of select host DNA repair and DNA damage checkpoint proteins. If the first hypothesis is correct (and the DNA damage is oxidative), the risk of chlamydia-associated cancers might be lowered by administration of antibiotics (to eliminate the chlamydiae) in combination with dietary anti-oxidants (like vitamins C or E) to inactivate the free radicals made during infection/inflammation. These studies may also ultimately help define the cancer risk for chlamydiae- infected individuals. RELEVANCE: The National Cancer Institute (NCI) estimates that there were11,150 new cases of cervical cancer and 3,670 deaths in 2007. The estimates for lung cancer in 2007 are 213,380 new cases resulting in 160,390 deaths. Although the primary risk factors are genital Human Papilloma Virus infection (for cervical cancer) and smoking (for lung cancer), approximately 10% (for cervical cancer) and 13% (for lung cancer) of cases develop in the apparent absence of these risk factors. This proposal will begin to evaluate the possibility that chlamydia infections may damage host cell DNA, leading to mutations and, possibly, to cancer. If so, these studies may have a significant impact on cancer prevention and risk assessment. PUBLIC HEALTH RELEVANCE: Recent data suggest that infections with the bacteria Chlamydia trachomatis or Chlamydia pneumoniae increase risk for developing cervical and lung cancer. Our studies will test the possibility that chlamydia infection damages the host's DNA, leading to mutations and, perhaps, to cancer. Because the National Cancer Institute (NCI) estimates that there were 11,150 new cases of cervical cancer (with 3,670 deaths) and 213,380 new cases of lung cancer (with 160,390 deaths) in 2007, these studies will significantly impact cancer prevention and risk assessment.